Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A. Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359. These patents disclose that azithromycin and certain derivatives thereof possess antimicrobial properties and are accordingly useful as antibiotics.
It is widely known that oral dosing of azithromycin can result in the occurrence, in some patients, of adverse gastrointestinal (GI) side effects, such as cramping, diarrhea, nausea, and vomiting. In combined clinical studies of azithromycin involving 3,995 patients (all dose levels combined), 9.6% of patients reported gastrointestinal side effects. The most frequent of these side effects were diarrhea (3.6%), nausea (2.6%), and abdominal pain 2.5%) (Hopkins, Am. J. Med. 91(suppl 3A) (1991) 40S–45S).
The incidence of gastrointestinal side effects is higher at higher doses than at lower doses. For example, a common 5 day course of azithromycin therapy consists of 500 mg on day 1 followed by 250 mg on days 2, 3, 4, and 5. For this course of therapy, the reported incidence of various, gastrointestinal side effects was 5% diarrhea/loose stools, 3% abdominal pain, and 3% nausea (Zithromax (Trademark of Pfizer Inc.) capsule package insert). After a single 1 g oral dose, the reported incidence of various gastrointestinal side effects was 7% diarrhea/loose stools, 5% nausea, and 2% vomiting (Zithromax capsule package insert).
It is also known that azithromycin can cause gastrointestinal side-effects in non-human mammals, e.g. dogs.
An improved dosage form of azithromycin which permitted oral dosing of high doses of azithromycin (e.g., 2 g) with relatively reduced side effects would permit wider application of single dose azithromycin therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Likewise, an improved dosage form which lowered the incidence of gastrointestinal side-effects at lower doses would also be of significant value.